Process for preparing 9, 11-oxido-steroids



United States Patent Claims priority, application Switzerland December -2-2, 1950 3 Claims. C1. 260-23955 .The ;present iinvention .isaconcerned with -a new ;,process leading to new compounds which .rnake it po ssibleao synthesize therapeutically active steroids containing oxygen in the ll-position.

The steroids with oxygen in ll-position are of great importance. An important representative of this class of compounds is for example cortisone, A -3,ll,20-trioxo- 17a,2l-dihydroxy-pregnene. The hitherto known processes for the synthetic production of such steroids use as starting materials desoxycholic acid and its derivatives, that is to say compounds which possess a hydroxyl group in 12-position. It has been shown however that the transfer of oxygen from the 12- to the ll-position is a very tedious process requiring several operations. In addition the desoxycholic acid used as starting material is only obtainable in relatively limited quantity, so that for example it is practically impossible to manufacture the cortisone required in therapy in suificient quantity by this method. A requirement therefore exists for new sources for the manufacture of this medicament. The easily available sterols, such as ergosterol, stigmasterol or sitosterol, but more especially cholesterol, have indeed for many years been important starting materials for the production of sex hormones. They have however hitherto been without importance for the production of compounds with oxygen in the ll-position of the intact steroid structure.

The present invention is based on the observation that by starting from the above-mentioned sterols or conversion products thereof, compounds of the steroid series with oxygen in the ll-position can be obtained when a A' -steroid is treated with an agent capable of introducing oxygen, the resultant 9,l1-oxido-7-oxo compound is isomerized land the oxo-group in 7-position of the resultant 7,11-dioxo-steroid is removed by reduction.

The process is illustrated by the following diagram of partial formulae Car 2,768,163 "Patented Oct. 23, 1956 =:pendin'g zapplioation S. N. 261,581, filed on even date :hrewithi) iwhich 'is5a recognized and well known interzinediatetfor' the 'productionof 1 the highly active hormone t1ladehydrocorticosterone (cf. Wettstein '& Meystre: tHelvAGhimfiActa, vol. 30, 'pp. 12624265 (1947 Aniotheriobject of the'invention is a-process for the manuta'etnreJot-9;1il=oxido 7-oxo-steroids. It comprises treat- :"ing .a .n steroid with hydrogen peroxide.

These A -stero'ids belong to the cyclopentanopolyhydropenanthrene or the polyhydrochrysene series. Pariticularrimportance is attached-to the derivatives or cholestane, coprostane, sitostane, stigmastane, -cholane, alloel'iol-anegpregnane,'androstaneand 'etiocholane. In additionjto'the aforementioned double'bo'nds, the starting mafterials mayhave other doublebonds. "Where any double ilionds are reactive these are suitably protected before i the oxidation ist-ep o'f the process, for example by attachment tof:halogen:'orahydrogen halide. 'For-theprotection of the 5,6 double ibond, A -steroids :may be converted into 'isteroids. They can be obtained, e. g. by dehydrogenating corresponding A -steroid with mercuric acetate, selenium dioxide or bromine.

For the oxidation according to the invention, hydrogen peroxide is used in the presence of a diluent, such as an organic solvent, e. g. acetic acid.

The following examples illustrate the invention, the relation between parts by weight and parts by volume being the same 'as that between the gram and the cubic centimeter:

Example 1 3.5 parts by weight of A -3,8-acetoxy-ergostatriene are suspended in 500 parts by volume of glacial acetic acid. To this suspension 66 parts by volume of an aqueous solution of hydrogen peroxide, containing 0.012 part by weight of active oxygen per part by volume, are added. The reaction mixture is mechanically shaken for 5 days whereby the undis-solved material goes into solution. At the end of the reaction period, the mixture is diluted with 1000 parts by volume of water and extracted with ether. The ethereal solution is washed with water, sodium bicarbonate solution and again with water, dried and evaporated. The crude product thus obtained is re crystallized from methanol, whereby A -3B-acetoxy-7- oxo-9,l1-oxido-erogstene of melting point 205 C. sepa rates in nice crystals.

By treating A -3,8-acetoxy-stigmastatariene with hydrogen peroxide under identical conditions A 3fi-'acetoxy-7-oxo-9,ll-oxido-stigmastene is obtained.

Example 2 1 part by weight of A' -3,B,20-diacetoxy-allo-pregnadiene, dissolved in parts by volume of glacial acetic acid, is mixed with 29 parts by volume of an aqueous solution of hydrogen peroxide, containing 0.012 part by weight of active oxygen per part by volume. The solution is then kept at room temperature for 6 days, diluted with 200 parts by volume of water and extracted with 800 parts by volume of ether in 3 portions. The combined ether extracts are washed with water, sodium bicarbonate solution and water, dried and evaporated. The residue is taken up in ether, concentrated to a small volume and diluted with hexane until the solution becomes cloudy. The mixture is then left at 0 C. for several hours whereupon the 3,3,20-diacetoxy-7-oxo-9Jl-oxido-allo-pregnane can be separated by filtration. The pure product shows no absorption maximum in the ultraviolet absorption spectrum.

In an analogous way A' -3/8,17 3-di'acetoxy-androstadiene is transformed into 318,17}9-diacetoxy-7-oxo-9,11- oxido-androstane.

Example 3 0.7 part by volume of methyl A' -3cr-acetoxy-choladienate is dissolved in 120 parts by volume of glacial acetic acid and diluted with 20 parts by volume of an aqueous solution of hydrogen peroxide, containing 0.012 part by weight of active oxygen per part by volume. The reaction mixture is left at room temperature for 5 days and then worked up exactly as described in Example 2. There is obtained a nearly colorless oil from which by crystallization from a mixture of acetone and hexane or ether and pentane methyl 3u-acet0xy-7-oxo-9,1l-oxidocholanate is isolated. In ethanolic solution no maximum is observed in the ultraviolet spectrum.

What is claimed is:

1. A method of converting a member selected from the group consisting of A -3-lower alkylcarbonyloxyergostadienes, A -3-lower alkylcarbonyloxy-stigmastadienes, A -3-lower alkylcarbonyloxy-allo-pregnadienes, A -3-lower alkylcarbonyloxy-androstadienes and A -3-lower alkylcarbonyloxy-choladienes to the corresponding 3-1ower alkylcarbonyloxy-oxo-9,1l-oxidocompounds, which comprises subjecting the said member of the said group to the action of hydrogen peroxide.

4 I 2. A'method of converting a lower alkyl A' -3- lower alkylcarbonyloxy-choladienate to the corresponding lower alkyl 3-lower alkylcarbonyloxy-7-oxo-9,11-

References Cited in the file of this patent UNITED STATES PATENTS 2,323,277 Miescher June 29, 1943 2,576,949 Levin Dec. 4, 1951 OTHER REFERENCES Fieser et al.: Natural Products Related to Phenanthrene, 3rd Ed, page 425 1949) 

1. A METHOD OF CONVERTING A MEMBER SELECTED FROM THE GROUP CONSISTING OF $7,8,9,11-3-LOWER ALKYLCARBONYLOXERGOSTADIENES, $7,8,9,11-3-LOWER ALKYLCARBONYLOXY-STIGMASTADIENES, $7,8,9,11,3-LOWER ALKYLCARBONYLOXY-ALLO-PREGNADIENES, $7,8,9,11-3-LOWER ALKYLCARBONYLOXY-ANDROSTADIENES AND $7,8,9,11-3-LOWER ALKYLCARBONYLOXY-CHLOADIENES TO THE CORRESPONDING 3-LOWER ALKYLCARBONYLOXY-OXO-9,11-OXIDOCOMPOUNDS, WHICH COMPRISES SUBJECTING THE SAID MEMBER OF THE GROUP TO THE ACTION OF HYDROGEN PEROXIDE. 